Composition of a superparamagnetic or ferromagnetic particle and an X-ray contrast agent for MRI

ABSTRACT

There is provided a magnetic resonance contrast medium comprising magnetically responsive particles and a physiologically tolerable osmoactive agent.

The present invention relates to improvements in and relating tomagnetic resonance imaging (MRI), and in particular to contrast mediafor use in MRI, especially of body cavities from which contrast mediamay be discharged from the body without passing through body tissue, inparticular the gastrointestinal (GI) system.

MRI is now a well established medical diagnostic tool which isparticularly attractive to physicians, at least in part due to itsability to differentiate between soft tissues and since it does notrequire the patient to be exposed to the potentially harmful ionizingradiation, e.g. X-radiation and gamma-radiation, of conventionalradiography.

Although MRI can be carried out without using added contrast media, ithas found that image contrast can be improved by administering to thepatient substances which affect the nuclear spin reequilibration of thenuclei (hereinafter the "imaging nuclei"--generally water protons inbody fluids and tissues) that are responsible for the magnetic resonance(MR) signals from which MR images are generated.

Accordingly, in recent years, many such substances have been suggestedfor use as MRI contrast agents. Thus, for example, in 1978 Lauterburproposed the use of paramagnetic species, such as Mn(II), as MRIcontrast agents (see Lauterbur et al., pages 752-759 in "Electrons toTissues--Frontiers of Biological Energetics", Volume 1, edited by Duttonet al., Academic Press, New York, 1978). More recently Schering AG, inEP-A-71564, proposed the use of the dimeglumine salt of thegadolinium(III) chelate of diethylenetri-aminepentaacetic acid(GdDTPA-dimeglumine).

While MRI has until now mainly been used for imaging the central nervoussystem, the technique has great potential for imaging externally voidedbody cavities and especially the GI tract. However, development of MRIas a technique for imaging the GI tract, or indeed the abdomen ingeneral, has been hindered by the special problems of imaging theabdomen in which, in the absence of a contrast agent, inter-tissuecontrast is relatively poor. There is thus a general need for improvedMRI contrast media suitable for imaging such body cavities.

Various substances have been evaluated as potential MRI contrast agentsfor the GI system, including for example paramagnetic compounds,perfluorochemicals and magnetically responsive particles (that isferromagnetic, ferrimagnetic or superparamagnetic particles). In thisregard, reference may be had to Wesbey et al. Radiology 149: 175-180(1983), Runge et al. Radiology 147: 789-791 (1983), Laniado et al.Fortschr. Rontgenstr. 147: 325-332 (1987), Kornmesser et al. Fortschr.Rontgenstr. 147: 550-556 (1987), Claussen et al. Fortschr. Rontgenstr.148: 683-689 (1988), Lonnemark et al. Acta Radiologica 29: 599 (1988),Lonnemark et al. Acta Radiologica 30: 193-196 (1989) Fasc. 2, Mattrey etal. AJR 148: 1259 (1987), and Wesbey et al. Magn. Reson. Imag. 3: 57-64(1985) and to references therein.

Two products at least are now in clinical trials as oral MRI contrastmedia--suspensions of magnetically responsive particles (see Lonnemarket al. (1989) supra) and solutions of GdDTPA-dimeglumine (see Claussenet al. supra).

From a diagnostic point of view, magnetically responsive particles andparamagnetic metal chelates such as GdDTPA produce completely differentcontrast enhancements in MR images. Thus GdDTPA is a "positive" contrastagent, i.e. its effect of reducing the spin-lattice relaxation time (T₁)of the imaging nuclei results in an iincrease in the image intensity forthe body regions into which it distributes. Magnetically responsiveparticles on the other hand are "negative" contrast agents, so calledsince their effect of reducing the spin-spin relaxation time (T₂) of theimaging nuclei outweighs the effect of T₁ reduction and results in adecrease in the MR signal intensity from the body regions into whichthey distribute.

The two forms of contrast enhancement are in fact complementary--forsome pathological structures positive MRI contrast media will giveclearer images and for others negative contrast media will give theclearer images. Indeed, in certain instances it is advantageous toadminister both positive and negative contrast agents to enhancecontrast in particular organs or tissues (see Hemmingsen et al. ActaRadiologica 30: 29-33 (1989) Fasc 1).

The contrast enhancing properties of these products also differ in otherways. Thus in general, paramagnetic, positive contrast agents have arelatively close range effect and need to be in close proximity (at themolecular level) to water molecules in order to be effective as contrastagents. Negative contrast agents in the form of magnetically responsiveparticles have a longer range effect and do not need to be closelyadjacent to water molecules or other protons (where the imaging is ¹ HMRI).

In the GI tract water is absorbed from the contents thus resulting in areduction in contrast efficiency of paramagnetic substances, especiallyin the lower part of the alimentary tract. This problem has beenaddressed by formulation of GdDTPA with an osmoactive agent, that is acompound which enhances water retention in the gut. Thus, for example,EP-A-124766 (Schering AG) and Claussen et al. (supra) report the resultsof investigations in which patients received an osmoactive oral positiveMRI contrast medium containing 1.0 mmol/l GdDTPA and 15 g/l mannitol.

The inclusion of such osmoactive compounds can however cause at leastmildly unpleasant side effects for the patients (13 of the 32 patientsin the Schering/Claussen et al. study suffered meteorism or diarrhoea),and the inclusion of such compounds in negative contrast media for whichthe normal absorption of water from the gut contents would notapparently pose a problem would therefore seem to be contraindicated.

We have, however, surprisingly found that formulation of magneticallyresponsive particles (MRP) with a physiologically tolerable osmoactiveagent significantly improves the diagnostic values of the MRP containingMR contrast media.

Thus, in one aspect, the present invention provides a contrast mediumcomprising magnetically responsive particles and a physiologicallytolerable osmoactive agent.

The osmoactive agent in the contrast media of the invention may be anyphysiologically tolerable osmotically active substance, such as forexample: inorganic salts (such as magnesium sulphate); polyols,particularly saccharides or sugar alcohols (see Kirk Othmer "ConciseEncyclopedia of Chemical Technology", page 55, John Wiley & Sons, NewYork) or physiologically tolerable salts thereof or of sugar aminoalcohols (especially hexitols such as mannitol or sorbitol); and X-raycontrast agents, especially iodinated water soluble X-ray contrastagents (such as non-ionic and ionic monomers and dimers, e.g. iohexol,diatrizoate meglumine and metrizoate sodium). Such monomers and dimersgenerally contain one or two triiodophenyl moieties in their molecularstructure.

Where X-ray contrast agents are used as osmoactive agents in the MRIcontrast media of the invention, there are advantages to both ionic andnon-ionic X-ray contrast agents. Thus using ionic X-ray contrast agents,a lower concentration can be used to achieve the same osmotic effect.However, non-ionics are especially suitable for contrast media foradministration to young children and persons with perfused or suspectedperfusion of the GI system because of the general lower toxicity ofnon-ionic agents. Another advantage of the non-ionic agents is that theydo not precipitate in the stomach.

Examples of suitable non-ionic X-ray contrast agents include, forexample, metrizamide (see DE-A-2031724), iopamidol (see BE-A-836355),iohexol (see GB-A-1548594), iotrolan (see EP-A-33426), iodecimol (seeEP-A-49745), iodixanol (see EP-A-108638), ioglucol (see U.S. Pat. No.4,314,055), ioglucomide (see BE-A-846657), ioglunioe (see(DE-A-2456685), iogulamide (see BE-A-882309), iomeprol (EP-A-26281),iopentol (see EP-A-105752), iopromide (see DE-A-2909439), iosarcol (seeDE-A-3407473), iosimide (see DE-A-3001292), iotasul (see EP-A-22056),iovarsul (see EP-A-83964) and ioxilan (see WO87/00757).

Where the X-ray contrast agent is ionic, the counterion should, ofcourse, be a physiologically tolerable ion, e.g. a metal ion such assodium, or an organic cation such as meglumine.

Particularly preferred osmoactive agents for the contrast media of theinvention include X-ray contrast agents, e.g. iohexol and metrizoate,especially non-ionic X-ray agents and saccharides such as mannitol.

Particular ionic X-ray contrast agents useful according to the inventionthus include physiologically acceptable salts of3-acetylamino-2,4-6-triiodobenzoic acid,3,5-diacetamido-2,4,6-triiodobenzoic acid,2,4,6-triiodo-3,5-dipropionamido-benzoic acid,3-acetylamino-5-((acetylamino)methyl)-2,4,6-triiodobenzoic acid,3-acetylamino-5-(acetylmethylamino)-2,4,6-triiodobenzoic acid,5-acetamido-2,4,6-triiodo-N-((methylcarbamoyl)methyl)-isophthalamicacid,5-(2-methoxyacetamido)-2,4,6-triiodo-N-[2-hydroxy-1-(methylcarbamoyl)-ethyl]-isophthalamicacid, 5-acetamido-2,4,6-triiodo-N-methylisophthalamic acid,5-acetamido-2,4,6-triiodo-N-(2-hydroxyethyl)-isophthalamic acid2-[[2,4,6-triiodo-3[(1-oxobutyl)-amino]phenyl]methyl]-butanoic acid,beta-(3-amino-2,4,6-triiodophenyl)-alpha-ethyl-propanoic acid,3-ethyl-3-hydroxy-2,4,6-triiodophenyl-propanoic acid,3-[[(dimethylamino)-methyl]amino]-2,4,6-triiodophenyl-propanoic acid(see Chem. Bet. 93: 2347 (1960)),alpha-ethyl-(2,4,6-triiodo-3-(2-oxo-1-pyrrolidinyl)-phenyl)-propanoicacid, 2-[2-[3-(acetylamino)-2,4,6-triiodophenoxy]ethoxymethyl]butanoicacid, N-(3-amino-2,4,6-triiodobenzoyl)-N-phenyl-β-aminopropanoic acid,3-acetyl-[(3-amino-2,4,6-triiodophenyl)amino]-2-methylpropanoic acid,5-[(3-amino-2,4,6-triiodophenyl)methylamino]-5-oxypentanoic acid,4-[ethyl-[2,4,6-triiodo-3-(methylamino)-phenyl]amino]-4-oxo-butanoicacid,3,3'-oxybis[2,1-ethanediyloxy-(1-oxo-2,1-ethanediyl)imino]bis-2,4,6-triiodobenzoicacid,4,7,10,13-tetraoxahexadecane-1,16-dioyl-bis(3-carboxy-2,4,6-triiodoanilide),5,5'-(azelaoyldiimino)-bis[2,4,6-triiodo-3-(acetylamino)methyl-benzoicacid], 5,5'-(apidoldiimino)bis(2,4,6-triiodo-N-methyl-isophthalamicacid), 5,5'-(sebacoyl-diimino)-bis(2,4,6-triiodo-N-methylisophthalamicacid), 5,5-[N,N-diacetyl-(4,9-dioxy-2,11-dihydroxy-1,12-dodecanediyl)diimino]bis(2,4,6-triiodo-N-methyl-isophthalamicacid),5,5'5"-(nitrilo-triacetyltriimino)tris(2,4,6-triiodo-N-methyl-isophthalamicacid), 4-hydroxy-3,5-diiodo-alpha-phenylbenzenepropanoic acid,3,5-diiodo-4-oxo-1(4H)-pyridine acetic acid,1,4-dihydro-3,5-diiodo-1-methyl-4-oxo-2,6-pyridinedicarboxylic acid,5-iodo-2-oxo-1(2H)-pyridine acetic acid, andN-(2-hydroxyethyl)-2,4,6-triiodo-5-[2,4,6-triiodo-3-(N-methylacetamido)-5-(methylcarbomoyl)benzamino]acetamido]-isophthalamicacid, as well as other ionic X-ray contrast agents proposed in theliterature e.g. in J. Am. Pharm. Assoc., Sci Ed. 42:721 (1953),CH-A-480071, JACS 78:3210 (1956), DE-A-2229360, U.S. Pat. No. 3,476,802,Arch. Pharm. (Weinheim, Ger) 306: 11 834 (1973), J. Med. Chem. 6: 24(1963), FR-M-6777, Pharmazie 16: 389 (1961), U.S. Pat. No. 2,705,726,U.S. Pat. No. 2,895,988, Chem. Ber. 93: 2347 (1960), SA-A-68/01614, ActaRadiol. 12: 882 (1972), GB-A-870321, Rec. Trav. Chim. 87: 308 (1968),East German Patent 67209, DE-A-2050217, DE-A-2405652, Farm Ed. Sci. 28:912(1973), Farm Ed. Sci. 28: 996 (1973), J. Med. Chem. 9: 964 (1966),Arzheim.-Forsch 14: 451 (1964), SE-A-344166, GB-A-1346796, U.S. Pat. No.2,551,696, U.S. Pat. No. 1,993,039, Ann 494: 284 (1932), J. Pharm. Soc.(Japan) 50: 727 (1930), and U.S. Pat. No. 4,005,188. The disclosures ofthese and all other documents cited herein are incorporated herein byreference.

The X-ray contrast agents are more preferred as osmoactive agents thanthe conventional osmoactive agents such as the mannitol used in theSchering/Claussen et al. studies since the side effects, meteorism anddiarrhoea, observed with mannitol should be reduced or eliminated.

The concentration of the osmoactive agent in the contrast media of theinvention may vary over a wide range and will be dependent on factorssuch as the chemical nature of the osmoactive agent, the physical andchemical nature of the MRP (e.g. the size of the magnetic particles) andthe other components within the contrast media, the intendedadministration route, and the pre-administration dilution ratio wherethe contrast medium is in concentrated form for dilution or dispersionprior to administration.

The appropriate concentration of an osmoactive agent for a contrastmedium can readily be selected on the basis of the known properties ofthe agent or with minimal routine experimentation. Conveniently,however, in a contrast medium ready for administration the osmoactiveagent will be present at a concentration of 10 to 800 mmol/l preferably30 to 400 mmol/l e.g. 2 to 370, especially 5 to 300 mgI/ml forosmoactive agents which are soluble iodinated X-ray contrast agents.

The contrast media of the invention also contains MRPs and there havebeen many suggestions of suitable MRPs for use as negative contrastagents in MRI. Reference may be had in this regard to the followingpublications: U.S. Pat. No. 4,863,715 (Jacobsen), WO85/02772 andWO89/03675 (Schroder), U.S. Pat. No. 4,675,173 (Widder), DE-A-3,443,252(Gries), U.S. Pat. No. 4,770,183 and WO 88/00060 (Groman), Lonnemark etal. (1989) supra, Laniado et al. (1987) supra, Widder et al. AJR 148:399-404 (1987), Widder et al. AJR 149: 839 (1988), Mendonca Dias et al.and Olsson et al. Society of Magnetic Resonance in Medicine (SMRM),London 1985, Edelman et al. and Williams et al. Radiology 161(P): 314(1986), Hahn et al. SMRM, Montreal 1986, Abstracts pages 1537-1538, Hahnet al. Radiology 164: 37 (1987), Hals et al. and Laniado et al. SMRM,Berkeley 1987, Niemi et al. Magnetic Resonance Imaging 6(Suppl. 1): 2(1988), Hahn et al. Magnetic Resonance Imaging 6(Suppl. 1): 78 (1988)and references therein.

Generally speaking, all such particles may be used in the compositionsof the invention. Thus the particles may be free or may be coated by orembedded in or on particles of a non-magnetic carrier material, e.g. anatural or synthetic polymer, for example, cellulose or a sulphonatedstyrene divinyl-benzene copolymer (see for example WO83/03920 ofUgelstad). The magnetically responsive particles may be ferromagnetic orferrimagnetic or may be sufficiently small as to be superparamagneticand indeed superparamagnetic particles are generally preferred.

Thus, the magnetically responsive particles used according to thepresent invention may be of any material which (although preferablynon-radioactive unless the particles are also intended to be detected bytheir radioactive decay emissions) exhibits ferromagnetism,ferrimagnetism or superparamagnetism. The particles may conveniently beparticles of a magnetic metal or alloy, e.g. of pure iron, butparticularly preferably will be of a magnetic compound such as aferrite, for example gamma ferric oxide, magnetite or cobalt, nickel ormanganese ferrites.

Particles such as those described by Ugelstad in WO83/03920, by Schroderin WO83/01738, WO85/02772 and WO89/03675, by Molday in U.S. Pat. No.4,452,773, by Widder in U.S. Pat. No. 4,675,173, by Groman in WO88/00060and U.S. Pat. No. 4,770,183, by Menz in WO90/01295 and by Lewis inW090/01899 or those such as Biomag M4200, AMI 26 and M 4125 availablefrom Advanced Magnetics Inc. of Cambridge, Mass., USA, are particularlysuitable for use in the compositions of the invention.

To avoid image distortion, it is preferred that the mean particle sizeof the magnetically responsive particles be less than about 5micrometers, preferably less than 1 micrometer and that the overall sizeof the non-magnetic carrier particles be less than 50 micrometers,preferably less than 20 micrometers, especially preferably 0.01 to 5micrometers, e.g. 0.1 to 5 micrometers. The magnetically responsiveparticles will generally have mean particle sizes in the range 0.002 to1 micromaters, preferably 0.005 to 0.2 micrometers.

Where the magnetically responsive particles are carried by carrierparticles, these are preferably of a material which is physiologicallytolerable and which is not biodegradable, at least in the environmentsit will experience on the way to and at the body cavity being imaged.

The contrast media of the invention may, of course, include componentsother than the osmoactive agents and MRPs, for example conventionalpharmaceutical or veterinary formulation aids such as wetting agents,disintegrants, binders, fillers, stabilizers, viscosity enhancingagents, flavouring agents, colouring agents, buffers, pH adjustingagents, and liquid carrier media.

The inclusion of buffers in the contrast media of the invention isparticularly preferred.

The inclusion of viscosity enhancing agents (e.g. natural, synthetic orsemi-synthetic high molecular weight substances, such as gums andpolysaccharides, guar gum, tragacanth, methyl cellulose, hydroxypropylcellulose, carboxymethyl cellulose, xanthan gum, alginates, kaolin,magnesium aluminium silicates and bentonite) in the contrast media ofthe invention is especially preferred. The viscosity enhancing agent, ifpresent, should be in a concentration sufficient to give the compositionthe desired viscosity. Desired viscosities can however vary over a broadrange depending, for example, on the segment of the GI tract which is tobe imaged. Compositions having viscosities of 200 to 5000, especially300-3000, cps are generally preferred; however, for certain usescompositions having much higher viscosities, e.g. up to 150000 cps oreven higher may be used. (Viscosities can conveniently be measured at20° C. using a Brookfield viscometer).

In one particularly preferred embodiment, the contrast media of theinvention are formulated to contain an incompletely hydrated viscosityenhancing agent, e.g. as a dry mix or as a suspension in which theviscosity enhancing agent is provided with a delayed release coating,e.g. of an Eudragit polymer. MRI contrast medium compositions containingincompletely hydrated viscosity enhancing agents are the subject of ourcopending British Patent Application No. 8916780.3 filed on Jul. 21,1989.

To improve contact between the MRPs and the walls of the gut (or otherbody cavity into which the contrast media are administered), thecontrast media of the invention may also advantageously contain amucoadhesive, for example, a polyacrylic acid or a derivative thereof,xanthan gum etc.

The contrast media of the invention may be formulated in aphysiologically tolerable aqueous carrier medium (e.g. as a suspensionor dispersion) ready for use or in concentrated form for dilution beforeuse. Concentrated products may readily be diluted, e.g. with water orjuice, prior to administration. Alternatively, the contrast medium ofthe invention may be formulated in dry from, e.g. in powder, granule,pellet or tablet from for dispersion before use.

The contrast media of the invention are particularly suited to use, ifnecessary after dispersion in aqueous media, as MRI contrast media forimaging of the gastrointestinal tract and in particular for imaging theduodenum and the intestines. For such a purpose the contrast medium maybe administered orally or rectally or by orally or rectally insertedtubes. However, as indicated above, the contrast media are of coursealso suitable for use in imaging other externally voided body cavitiessuch as the bladder, uterus and vagina.

Thus, viewed from another aspect, the invention provides the use of aphysiologically tolerable osmoactive agent for the manufacture of acontrast medium for use in magnetic resonance imaging.

Viewed from a further aspect, the invention provides the use ofmagnetically responsive particles for the manufacture of a contrastmedium for use in magnetic resonance imaging.

Viewed from a yet further aspect, the present invention provides amethod of generating a magnetic resonance image of a human or non-human,e.g. mammalian, subject in which method a contrast medium comprisingmagnetically responsive particles and an osmoactive agent isadministered into an externally voided body cavity of said subject (e.g.the gastrointestinal tract).

Viewed from a yet still further aspect, the invention provides adiagnostic contrast agent kit comprising a plurality of magneticallyresponsive particles and, packaged separately thereto, a physiologicallytolerable osmoactive agent.

In the method of the invention the dose of the contrast medium willgenerally be at least 30 ml for an adult human subject and more usually200 to 1500 ml, especially 300 to 1000 ml. In this the magneticallyresponsive particles will generally be contained at a concentration of0.01 to 10 g/liter, preferably 0.05 to 3 g/liter, e.g. 0.1 to 3 g/liter.The dose may be taken in portions, e.g. for oral administration about2/3 being ingested 20 minutes before imaging and the remainder beingingested immediately before the subject is placed in the imager.

The invention is further illustrated by the following non-limitingexamples:

EXAMPLE 1

    ______________________________________                                        Suspension for Oral Administration                                            ______________________________________                                        Magnetic particles* 10.0       g                                              Hydroxyethyl cellulose                                                                            10.0       g                                              Methyl parahydroxybenzoate                                                                        0.8        g                                              Propyl parahydroxybenzoate                                                                        0.2        g                                              Ethanol             10.0       g                                              Mannitol            15.0       g                                              Saccharin sodium    1.0        g                                              Orange essence      0.3        g                                              Apricot essence     0.7        g                                              Water               952.0      g                                              ______________________________________                                    

The hydroxyethyl cellulose was dispersed in water with stirring for 2hours. Saccharin sodium, mannitol and a solution of the essences, andmethyl and propyl parahydroxybenzoate in ethanol were slowly added. Themagnetic particles were dispersed in the solution under vigorousstirring. The suspension contained 0.05 mg Fe/g.

EXAMPLE 2

    ______________________________________                                        Suspension for Rectal Administration                                          ______________________________________                                        Methyl parahydroxybenzoate                                                                        85         mg                                             Propyl parahydroxybenzoate                                                                        1          mg                                             Metrizoate sodium   10         g                                              Methyl cellulose    2          g                                              Magnetic particles* 0.5        g                                              Water               90         ml                                             ______________________________________                                         *The magentic particles were Biomag M4200 superparamagnetic particles         available from Advanced Magnetics Inc., Cambridge, Massachusetts, U.S.A. 

The methyl and propyl parahydroxybenzoates were dissolved in the waterat 90° C. After cooling, the metrizoate sodium (prepared according toU.S. Pat. No. 3,476,802) and methyl cellulose were added and the mixturewas agitated for 2 hours. The magnetic particles were suspended in themixture and the suspension was filled into a 100 ml tube. The suspensioncontained 0.2 mg Fe/ml.

We claim:
 1. A contrast medium for enteral use comprisingsuperparamagnetic, ferrimagnetic and ferromagnetic particles and, as aseparate chemical entity, a physiologically tolerable osmoactiveiodinated X-ray contrast agent, wherein said osmoactive agent is presentat a concentration of 10-800 mmol/l.
 2. A contrast medium as claimed inclaim 1, wherein said particles are coated by or embedded in or onparticles of a physiologically tolerable non-magnetic carrier material.3. A contrast medium as claimed claim 1 containing superparamagneticparticles.
 4. A contrast medium as claimed in claim 1 containingparticles of material selected from ferrite, gamma ferric oxide,magnetite and cobalt, nickel and manganese ferrites.
 5. A contrastmedium as claimed in claim 1, wherein said particles have a diameter ofless than 5 micrometers.
 6. A contrast medium as claimed in claim 1further containing a physiologically tolerable viscosity enhancingagent.
 7. A method of generating a magnetic resonance image of a humanor nonhuman mammalian body, said method comprising administering to anexternally voided body cavity of said body a contrast medium as claimedin claim 1 and generating a magnetic resonance image of at least part ofsaid body.
 8. A contrast medium as claimed in claim 2 containingparticles of material selected from ferrite, gamma ferric oxide,magnetite and cobalt, nickel and manganese ferrites.
 9. A contrastmedium as claimed in claim 3 containing particles of material selectedfrom ferrite, gamma ferric oxide, magnetite and cobalt, nickel andmanganese ferrites.
 10. A contrast medium as claimed in claim 2 whereinsaid particles have a diameter of less than 5 micrometers.
 11. Acontrast medium as claimed in claim 3 wherein said particles have adiameter of less than 5 micrometers.
 12. A contrast medium as claimed inclaim 4 wherein said particles have a diameter of less than 5micrometers.
 13. A contrast medium as claimed in claim 2 furthercomprising a physiologically tolerable viscosity enhancing agent.
 14. Acontrast medium as claimed in claim 3 comprising a physiologicallytolerable viscosity enhancing agent.
 15. A contrast medium as claimed inclaim 4 further comprising a physiologically tolerable viscosityenhancing agent.
 16. A contrast medium as claimed in claim 5 furthercomprising a physiologically tolerable viscosity enhancing agent.
 17. Amethod of generating a magnetic resonance image of a gastrointestinaltract of a human or non-human mammalian body, said method comprisingadministering to the gastrointestinal tract a contrast medium as claimedin claim 1 and generating a magnetic resonance image of thegastrointestinal tract.
 18. A method according to claim 17 wherein theiodinated X-ray contrast agent is non-ionic.
 19. A diagnostic contrastagent kit comprising a plurality of superparamagnetic, ferrimagnetic orferromagnetic particles and, packaged separately thereto, aphysiologically tolerable osmoactive agent.